PROJECT SUMMARY Colorectal cancer (CRC) is the third most common cancer among men and women in the United States, and it is critical that we identify safe, effective, and easily implemented preventive strategies. Recent evidence has emerged to suggest that use of glucosamine and chondroitin supplements is associated with reduced inflammation and risk of CRC. Given that inflammation has been implicated in the etiology of CRC, this may represent the mechanism by which these popular, non-vitamin, non-mineral supplements may act to reduce risk of CRC. With excellent safety profiles, glucosamine and chondroitin may be ideal candidates for a potential preventive strategy. Little is known, however, about when and how these popular supplements affect inflammation and subsequent colorectal carcinogenesis. To date, no study has evaluated whether use of these supplements is associated with risk of the CRC precursor lesion, colorectal adenoma. Evidence of an association with adenoma would suggest that glucosamine and chondroitin act early in the process of carcinogenesis, thereby making these popular supplements a potential candidate for an adenoma prevention trial. Furthermore, despite evidence to suggest that use of these supplements is associated with reduced inflammation in humans, it is unknown if this association varies by supplement form (ie, glucosamine hydrochloride vs glucosamine sulfate), formulation (ie, glucosamine alone vs glucosamine + chondroitin), and dose. Should the association continue to indicate a chemopreventive effect, addressing whether the association with inflammation varies by supplement form, formulation, and dose will help inform the development of an appropriate intervention strategy. We therefore propose the first-ever study examining the association between use of glucosamine and chondroitin supplements and risk of adenoma (Aim 1). Among nearly 44,000 persons screened for colorectal cancer between 2002 and 2012 in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS), high-risk adenomas (n=1,643) will be compared with screen-negative controls in terms of prior glucosamine and chondroitin use. We further propose to use nationally representative data on over 27,000 adults from the National Health and Nutrition Examination Survey (NHANES) to evaluate whether the association between use of glucosamine and chondroitin supplements and inflammation, as measured by C- reactive protein concentration, varies by supplement form, formulation, and dose (Aim 2). Given the consistent and promising evidence to suggest that these supplements may reduce inflammation and risk of CRC, it is critical that we elucidate how and when these supplements act to affect inflammation and subsequent colorectal carcinogenesis. Such information is critical to informing our understanding of the chemopreventive potential of these supplements and can guide the development of future preventive efforts.